Toshihiko Sumii

Autoimmune pancreatitis as a new clinical entity : Three cases of autoimmune pancreatitis with effective steroid therapy

The most common forms of chronic pancreatitisare related to alcohol ingestion, whereas the entity ofnon-alcohol-associated (idiopathic) pancreatitis ispoorly understood. Autoimmunity has been suggested as a possible etiologic factor of idiopathicchronic pancreatitis. A total of 362 Japanese patientsunderwent endoscopic retrograde pancreatography (ERP)for suspected pancreatic disease, and 161 were diagnosed with chronic pancreatitis. Among them, we foundthree cases (1.86% incidence) of unique chronicpancreatitis, in which ERP revealed diffuse narrowing ofthe main pancreatic duct with an irregular wall. We diagnosed these three patients as havingpancreatitis associated with an autoimmune mechanismmorphologically and biochemically and started them onsteroid therapy. The characteristics of the these three patients were as follows:hypergammaglobulinemia, eosinophilia, ultrasonographyshowing hypoehoic diffuse swelling in the pancreas(sausage-like appearance), ERP showing diffuse narrowingof the main pancreatic duct with irregular like thumbprintlike marks,reversible exocrine insufficiency, and positiveanti-carbonic anhydrase II antibody. After one month ofthe treatment with steroids, pancreatitis dramatically improved morphologically and enzymatically.Here we describe these cases of the suspected autoimmunechronic pancreatitis. We must recognize the concept andthe features of autoimmune pancreatitis in order to avoid unnecessary surgery as pancreaticcancer.

Intraductal papillary-mucinous tumors of the pancreas: differential diagnosis between benign and malignant tumors by endoscopic ultrasonography.

Intraductal papillary-mucinous tumors of the pancreas: Differential diagnosis between benign and malignant tumors by endoscopic ultrasonography

Evaluation of pancreatic endocrine and exocrine function in patients with autoimmune pancreatitis.

Objectives: Up to now, the characteristics of pancreatic endocrine and exocrine functions in autoimmune pancreatitis (AIP) are still unclear. The aim of this study is to evaluate pancreatic functions in AIP compared with those of chronic pancreatitis (CP). Methods: Twelve patients with AIP and 25 patients with CP were examined for exocrine and endocrine pancreas. Exocrine function was evaluated by a secretin test. Concerning endocrine function, insulin secretion (C-peptide response) was examined with the glucagon tolerance test and glucagon secretion was examined with the arginine tolerance test. Pathological examination of pancreatic tissues was done on the operative specimens of AIP and CP that could not be clinically excluded from pancreatic cancer. Results: For the secretin test, 8.3% of patients with AIP showed 1-factor abnormality, which was a reduction in volume, and 41.7% showed 2-factor abnormalities, which were a reduction in volume and amylase output. On the other hand, 44.0% of patients with CP showed only 1-factor abnormality, which was the reduction in the maximum bicarbonate concentration. Autoimmune pancreatitis accompanied with diabetes mellitus showed a reduction both in &Dgr;C-peptide response (&bgr;-cell response) and &Dgr;glucagon (&agr;-cell response). Histologically, AIP showed lymphoplasmatic cells infiltration surrounding the pancreatic ducts, but basement membranes were intact. Moreover, basement membranes of the duct were injured in CP. Furthermore, islet cells in AIP were revealed as almost intact even though they were surrounded by fibrosis. Conclusions: These findings indicate that exocrine dysfunction with AIP is different from CP because AIP induces stenosis of the pancreatic ducts, but ductal cells that possess the function of bicarbonate secretion are intact, and that endocrine dysfunction with AIP was secondary pancreatic diabetes.

Expression and diagnostic evaluation of the human tumor-associated antigen RCAS1 in pancreatic cancer

Introduction Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is one of the membrane molecules expressed on human cancer cells and is presumed to play a protective role for tumor cells against immune surveillance by inhibition of clonal expansion and induction of cell death in immunocytes. Aims To address whether RCAS1 is expressed in pancreatic cancer and whether serologic diagnostic evaluation is useful compared with that of carbohydrate antigen 19–9 (CA19–9) and soluble Fas ligand. Methodology Immunohistochemical expression of RCAS1 was examined by staining with a 22–1-1 monoclonal antibody, and serum RCAS1 concentrations were determined by an enzyme-linked immunosorbent assay in 20 cases of ductal adenocarcinoma of the pancreas and other pancreatic diseases. Results Immunohistochemically, RCAS1 detection occurred in 100% (20/20) of ductal adenocarcinoma of the pancreas cases, 100% (6/6) of intraductal papillary–mucinous adenoma of the pancreas cases, and 40% (2/5) of chronic pancreatitis cases. RCAS1 was found in the cytoplasm of cancer cells and ductal cells. Serum RCAS1 concentrations in patients with ductal adenocarcinoma of the pancreas were significantly higher than those in patients with chronic pancreatitis (p < 0.0001), acute pancreatitis (p < 0.005), and autoimmune pancreatitis (p < 0.001). RCAS1 concentrations in patients with intraductal papillary–mucinous adenoma of the pancreas were also significantly higher than those in patients with chronic pancreatitis (p < 0.05) and autoimmune pancreatitis (p < 0.05). Positive serum RCAS1 samples (concentration, ≥10 U/mL) were found most often in cases of pancreatic neoplasm (80% [16/20], ductal adenocarcinoma of the pancreas; and 60% [3/5], intraductal papillary–mucinous adenoma of the pancreas). By contrast, in cases of pancreatic inflammatory diseases, raised concentrations occurred in 9.4% (3/32) of chronic pancreatitis cases, none (0/6) of acute pancreatitis cases, and none (0/8) of autoimmune pancreatitis cases. The sensitivity of CA19–9 for ductal adenocarcinoma of the pancreas was 75% and the specificity was 73.1% compared with chronic pancreatitis. On the other hand, the sensitivity of RCAS1 for ductal adenocarcinoma of the pancreas was 80% and the specificity was 96.2% compared with chronic pancreatitis. The specificity of RCAS1 for chronic pancreatitis was higher than that of CA19–9. Serum soluble Fas ligand concentrations were not considerably different among these patients. Conclusions RCAS1 was highly expressed in ductal adenocarcinoma of the pancreas, and serum RCAS1 concentrations in patients with ductal adenocarcinoma of the pancreas were significantly higher than those in patients with other inflammatory pancreatic diseases. Our results indicate that serum RCAS1 concentrations could be a new marker in screening procedures for pancreatic cancer.

Role of local pancreatic blood flow in development of hemorrhagic pancreatitis induced by stress in rats.

Our previous data showed that the pancreatitis induced in rats by cerulein develops into hemorrhagic pancreatitis following water-immersion stress. The present study examined the effects of water-immersion stress and high doses of cerulein (intraperitoneal injection) on pancreatic blood flow. Five hours of water-immersion stress reduced the local pancreatic blood flow to ∼30% of the initial value (253.75 ± 12.58 m;/min/100 g) without causing any histological alterations. Blood flow was decreased as early as 1 h after the immersion and reached the lowest value (30% of initial value) 3 h after the immersion. The administration of 40 μg/kg body wt cerulein as two intraperitoneal injections reduced the pancreatic blood flow by 40% 5 h after the first cerulein injection. The injections of cerulein combined with waterimmersion stress did not reduce the pancreatic blood flow more than did water-immersion stress alone. The systemic blood pressure was unaffected during 5 h of water immersion after the cerulein injections. These findings suggest that in rats the stress-induced decrease of local pancreatic blood flow may not produce pancreatitis, but may aggravate an existing acute pancreatitis.

Acute pancreatitis induced by cyclosporin A under stimulation of pancreas by Caerulein

Our purpose was to investigate enzymatically and morphologically the acute effect of the immunosuppressive agent cyclosporin A (CsA) on the exocrine pancreas of rats. The intravenous injection of CsA 10 and 20 mg/kg body weight (BW) increased the content of pancreatic amylase and protein and decreased the content of pancreatic DNA. Histologically, we observed intraacinar vacuolization and individual cell necrosis. Under stimulation of the pancreas by two intraperitoneal injections of caerulein 5 μg/kg BW at 1-h intervals (which did not induce any evident change in the pancreas), CsA induced a significant increase in serum amylase and in pancreatic wet weight in a dose-dependent manner. CsA at doses of 10 and 20 mg/kg BW produced a significant increase in the content of pancreatic amylase and protein. Macroscopically, we observed marked pancreatic edema, venous dilatation, and patchy hemorrhage. Histologically, there were significant differences in the seventy of intra-acinar vacuolization, interstitial edema, neutrophil infiltration, individual cell necrosis, and hemorrhage, severity of which was dose dependent. Pancreatic ductal erosion was particularly marked following treatment with CsA 20 mg/kg BW. These findings indicate that CsA accelerates abnormal pancreatic enzyme secretion and suggest that the therapeutically recommended doses of CsA can induce acute pancreatitis under stimulation of the pancreas.

Serum protease inhibitor capacity for elastase and the severity of pancreatitis.

To clarify the relationship between the diminution of the serum protease inhibitor capacity and the severity of pancreatitis, the binding capacity of serum protease inhibitors for exogenous elastase 1 (El) was investigated by gel filtration, the elastase activity of the a,-macroglobulin (α,-M)-elastase complex was measured, and the relationship between these findings and the severity of pancreatitis was studied in 13 patients with pancreatic disease and 6 healthy subjects. When 125I-labeled El was added to the sera of healthy subjects, it bound to α2-M and α1-protease inhibitor (α1-PI) with a mean ratio of 72:28. In mild acute pancreatitis (n = 9, the binding capacity of α2-M was less than that in healthy subjects. In severe pancreatitis (n = 4), most of the exogenous El bound to α1-PI (α2-M vs. (α2-PI, 13237). This diminution in the binding capacity of α2-M correlated well with the severity of acute pancreatitis. In the sera of patients (n = 4) with pancreatic cancer containing much immunoreactive El, the proportion of exogenous El bound by α2-M and α2PI (25:75) was similar to that seen in severe acute pancreatitis. A significant inverse relationship between the binding capacity of α2-M and the activity of the endogenous elastase bound to α2-M was seen in various pancreatic diseases. These findings suggest that in acute pancreatitis, the decreased binding capacity of serum α2-M and the increased enzymatic activity of the α2-M-protease complex correlate with the severity of the pancreatitis. In pancreatic cancer, however, this is not necessarily the case.

Alteration of cholecystokinin receptor binding after caerulein-induced pancreatitis in rats.

The alteration of CCK receptor binding on the pancreatic acini in vitro following the induction of pancreatitis was investigated in male rats. Pancreatitis was induced by administering 5 intraperitoneal injections of caerulein, 40 micrograms/kg each at hourly intervals. The uptake of [3H]-thymidine in the pancreatic acini increased on day 7 following caerulein administration. The release of amylase stimulated by CCK-8, and CCK receptor analysis using bioactive [125I]-BH-CCK-8, were performed at regeneration stage, on days 14 and 28 following the injections. The maximal release of amylase stimulated by CCK-8 was reduced on day 14 by about 40% and recovered on day 28. On day 14 there was a decrease of 60% in the number of high-affinity receptors and an increase of 161% in the number of low-affinity receptors. On day 28 there was a 128% increase in the number of low-affinity receptors. Accordingly, we suggest that the CCK receptors of the regenerating cells following caerulein-induced pancreatitis differ from those of the intact cells.

Appearance mechanism and molecular heterogeneity of serum pancreatic secretory trypsin inhibitor (PSTI).

SummarySerum immunoreactive pancreatic secretory trypsin inhibitor (PSTI) was measured by RIA. Serum PSTI levels were elevated in case of acute pancreatitis (15 of 15 cases: 317.7 ± 155.6 ng/ml: Mean ± SE) or pancreatic carcinoma (16 of 25 cases: 71.8 ± 17.1 ng/ml), and in those with chronic renal failure (6 of 6 cases: 412.8 ± 98.2 ng/ml). The molecular heterogeneity of elevated serum PSTI in such diseases was studied using chromatofocussing column chromatography. The results showed that serum PSTI was free from trypsin(-ogen) and was composed of at least three molecular forms of different isoelectric points. Two major forms were eluted around pH 8.2 (peak I) and 7.5 (peak II), with one minor form around pH 6.9 (peak III) from the column. The relative ratio of three forms differed with the disease state.Peak I was high in patients with pancreatic carcinoma, and peak II was high in patients with acute pancreatitis.

The time course of gap-junctional protein connexin 32 expression in the pancreas after the induction of acute pancreatitis by caerulein in rats

Background:Background: We previously demonstrated that the immunostaining of the gap-junction protein, connexin 32 (Cx 32), in the pancreas was markedly reduced in caerulein (Cn)-induced acute pancreatitis. The expression of Cx 32 in the pancreas during the course of acute pancreatitis is unclear. To address this, we examined Cx 32 mRNA and protein expression in the pancreas. Methods: Cx 32 mRNA and protein expression in the pancreas was examined by Northern blot analysis and Western blot analysis, respectively, 1, 4, 7, and 14 days after the induction of acute pancreatitis. Results: Cx 32 mRNA was identified in normal rat pancreas, and the value for the relative intensity against 18S rRNA was 0.57 ± 0.15 (mean ± SD). After the induction of acute pancreatitis by caerulein, the Cx 32 mRNA expression levels were increased on day 1, day 4, day 7, and day 14 compared with levels in the normal pancreas (1.63-fold, 1.61-fold, 1.49-fold, and 1.35-fold, respectively). A significant increase in Cx 32 protein expression was detected on day 1 and day 4 (1.67 ± 0.15-fold and 1.72 ± 0.2-fold, respectively), while Cx 32-positive spots, determined by immunohistochemical analysis, were markedly decreased on day 1 and had returned to normal by day 14. Conclusions: These results show that the expression of Cx 32 increases early on after the induction of pancreatitis by Cn, and that the normalization of Cx 32-immunostained spots in Cn-induced acute pancreatitis occurs after the increase in Cx 32 mRNA and protein expression.